As the United States continues to grapple with a relentless opioid crisis, physicians and researchers are increasingly promoting the use of antidepressants, specifically Selective Norepinephrine-Reuptake Inhibitors (SNRIs), for chronic pain treatment. This advocacy is gaining momentum even though the efficacy of these antidepressants for this particular use is yet to be definitively proven.
While studies have shown that Selective Serotonin-Reuptake Inhibitors (SSRIs), another class of antidepressants, “have little efficacy in treating chronic pain when compared to placebo or tricyclic antidepressants,” new research, led by Christopher Robinson of Beth Israel Deaconess Medical Center and Harvard Medical School, hypothesizes that SNRIs may be able to increase the modulation of pain across neurological pathways due to the increased uptake of norepinephrine.
In a recent publication, the authors elaborate on the shifting landscape of pain management:
“Generally, the treatment options for chronic and neuropathic pain include physical therapy, pain psychology, medical management, and interventional therapy, including surgical interventions. Various pain medications have been trialed with an increasing use of membrane stabilizers and antidepressants to treat neuropathic pain conditions. In recent years, antidepressants such as serotonin noradrenaline reuptake inhibitors (SNRIs) have been used to treat a wide range of pain conditions in addition to their use for depressive disorders but at lower doses for analgesia with a different risk profile and side effects at these doses.”
As the medical community seeks to address the opioid crisis, the risks and benefits of potential alternatives like antidepressants must be thoroughly scrutinized and validated through rigorous research.
To expand knowledge about alternative medications used in the management of chronic pain, the researchers reviewed studies on the efficacy of three SNRIs when used for chronic pain: duloxetine (brand name Cymbalta), venlafaxine (brand name Effexor), and milnacipran (brand name Savella). Specifically, they looked at the research regarding the effectiveness of the drugs on “musculoskeletal pain (chronic low back pain and osteoarthritis), fibromyalgia, and neuropathic pain conditions (peripheral diabetic neuropathy).”
“Typical doses for chronic musculoskeletal and neuropathic pain are 30-60 mg once a day. Common side effects, which are similar for most SNRIs, include headache, drowsiness, insomnia, fatigue, nausea, weight loss, weakness, change in libido; serious, though rare, side effects include suicidality, hepatoxicity, serotonin syndrome, and hyponatremia.”
According to the researchers, duloxetine may be useful in pain management for up to 48 weeks for patients with chronic knee osteoarthritis and chronic back pain. The dosage is administered at 60 mg/day; at that level, patients experienced a statistically significant reduction in pain levels. A double-blind, placebo-controlled study also found that duloxetine can be used to control peripheral diabetic neuropathy (PDN). Using the 24-hour pain score (“In the past 24 hours, how high was your worst level of pain”) along an 11-point Likert Scale. However, an increase in dosage did not lead to a correlated decrease in pain levels. Instead, doubling the 60mg/day dose maintained the same level of pain reduction.
A similarly structured study on the effectiveness of duloxetine in treating pain from fibromyalgia found no statistically significant reduction in pain over a 14-week period. Yet, “despite no improvement in pain scores, secondary outcome measures such as quality of life and safety outcomes showed significant findings in the duloxetine group. It demonstrated that they might have potential use in the overall symptomatic improvement in patients receiving duloxetine.” Meaning that symptoms secondary to chronic pain, such as depression, energy levels, and mobility concerns, may have been helped by the medication.
A double-blind, placebo-controlled study on the effects of venlafaxine on diabetic neuropathy found statistically significant changes in the pain scores of patients with this condition, depending on the dosage of the drug. Reductions in pain were found for 27% of patients in the placebo group, 32% in the group that was administered 75mg of the drug, and 50% in the group that was administered 150-225mg of the drug. For other neuropathic conditions, a systematic review found that venlafaxine was “nonsuperior” (not better) than other medications that are usually prescribed for chronic pain.
Interestingly, milnacipran is an SNRI that is not primarily used as an antidepressant. “Milnacipran is an SNRI used to treat fibromyalgia and occasional off-label use to treat depression. It effectively improves pain, fatigue, and function in patients with fibromyalgia.” However, while a 2012 meta-analysis showed decreased pain in patients with fibromyalgia and neuropathic pain, it also found increased rates of side effects in these patients.
“Oddly, patients who experienced early side effects of duloxetine (nausea, constipation, and drowsiness) appeared to have a more significant reduction in pain as those who did not, suggesting that adherence despite early side effects can result in increased improvement in pain.”
As has been written about before, an issue using double-blind, placebo studies for medications has to do with side effects. People can deduce when they are on the actual medication if they experience the side effects found within that class of drug. When it comes to antidepressants, many people are aware of these side effects, not just from informed consent but also from anecdotal evidence and the massive marketing campaigns pharmaceutical companies have produced for these drugs.
What is interesting here is that the researchers did not at least account for this possibility. As Wideman et al. note, “Pain is defined as a subjective experience, which means that it cannot be directly observed by those who are not experiencing it. Yet, clinicians and researchers rely upon observations and measures to assess and infer the pain experienced by other people.” Therefore, it is possible that patients with side effects knew they were on medication, and that knowledge can lead to the placebo effect. Instead, the researchers suggest that patients be pushed through the side effects for the possibility of some pain relief.
However, that pain relief itself is not built on solid evidence. For example, when used for fibromyalgia, duloxetine correlated with an increase in participants’ “secondary measures” or quality of life measures. Yet, these participants did not report any significant decrease in pain. In fact, the researchers conclude that “the direct correlation between SNRIs and pain relief in chronic pain fibromyalgia patients is yet to be found.”
When it comes to milnacipran, the one drug within this research whose primary usage is neuropathic pain, there is evidence using fMRIs of increased activity in areas of the brain thought to be correlated with pain inhibition. However, “there was no statistically significant decrease in pain sensitivity in patients taking milnacipran compared to the placebo.” This drug has been marketed specifically for its use in neuropathic pain, yet limited evidence supports its capability to do just that.
Due to the ongoing overdose epidemic, there is a push to identify alternative treatments for chronic pain. As part of that push, many physicians are seeking non-opioid medications, either voluntarily or through pressure from the government, to offer their chronic pain patients. This includes pushing many people out of opioid therapy who were stable and healthy while taking the medication.
If patients are being pushed onto alternative medications, the research must be conclusive that the medications will work for their needs. Pushing patients onto alternative medications and treatments simply due to a social rise in “opioid phobia” has worsened outcomes in many chronic pain patients. If the alternatives have not been proven to be efficacious, these adverse outcomes could worsen care for people with chronic pain.
Robinson, C., Dalal, S., Chitneni, A., Patil, A., Berger, A. A., Mahmood, S., … & Hasoon, J. (2022). A look at commonly utilized serotonin noradrenaline reuptake inhibitors (SNRIs) in chronic pain. Health Psychology Research, 10(3). (Link)